1. Field of the Invention
This invention relates to novel derivatives of imidazoledicarboxylic acids and more particularly to such derivatives which are useful in preparing modified penicillins and cephalosporins. The invention also relates to a process for producing modified penicillins and cephalosporins and the like using the novel reactive derivatives of imidazoledicarboxylic acids.
2. Description of the Prior Art
Among the penicillins and cephalosporins which are useful antibiotics are those which contain an amino acid substituent at the 6(7)-amino group. These may be represented by the formula: ##STR2## wherein A is an organic radical selected from the group consisting of: ##STR3## Z is selected from the group consisting of hydrogen, acyloxy such as acetoxy, carbamoyloxy, heteroaromatic thio such as 5-(1-methyltetrazolyl)thio and quaternary ammonium such as substituted or unsubstituted pyridinium, quinolinium or picolinium.
These aminopenicillins and cephalosporins are prepared by coupling an alpha-amino acid to the amine group in the 6(7)-position. Amino acids used for preparing such alpha-aminopenicillins and cephalosporins include phenylglycine, (4-hydroxyphenyl)glycine, and the like. These amino acids may be of the L-, D-, or DL-configuration. In many cases, the D-configuration has superior antibacterial activity.
It is known that the antibacterial activity of penicillins and cephalosporins of this type can be increased by further modification of the molecule with an imidazoledicarboxylic acid to produce an antibiotic having the following formula: ##STR4## wherein R and A have the signification defined above. Antibiotics of this formula are disclosed in Japanese Published patent application No. 5974/1979 (German Offenlegungsschrift No. 28 26 546). These antibiotics have superior antibacterial activity especially against Pseudomonas aeruginosa, as compared with the unmodified penicillins and cephalosporins.
These improved antibiotics can be prepared by preparing a reactive derivative of an imidazoledicarboxylic acid of the formula: ##STR5## for example, the acid chloride thereof, and condensing this reactive derivative with alpha-aminopenicillins or cephalosporins having the general formula: ##STR6## wherein A and R are as defined above. However, when the condensation reaction is carried out using known reactive derivatives of the imidazoledicarboxylic acid such as the acid chloride derivative, the process has a number of drawbacks. It has been found that more than 2 moles of the acid chloride is needed per 1 mole of aminopenicillin or cephalosporin, many side reactions are encountered and the yield is low. For example, in the process disclosed in Japanese Published patent application No. 5974/1979, which uses the acid chloride derivative of the imidazoledicarboxylic acid, the yield ranges from 10 to 40%.
Hence, a need has continued to exist for an improved method for preparing alpha-amino penicillins and cephalosporins modified with imidazole dicarboxylic acids.